The mechanisms of cadmium carcinogenesis are under active investigation. Repeated subcutaneous injections of cadmium resulted in a rapid onset and high incidence of highly malignant tumors at the injection site and had an apparent association with malignant testicular tumors. The Syrian hamster was shown to be susceptible to cadmium-induced testicular carcinogenesis, while mice strains resistant to the acute effects of cadmium in the testes proved resistant also to its carcinogenic effects. Chronic oral exposure to cadmium in rats was associated with prostatic tumors, providing further evidence for a link between cadmium and prostatic carcinogenesis. Zinc was shown to inhibit cadmium carcinogenesis in a route- and site-dependent manner. Rare testicular tumors were also observed in rats in association with cadmium treatment including sertoli cell tumors, rete testis adenocarcinoma and seminomas, indicating a general susceptibility within the cells of the testes. A marked enhancement of cadmium cellular efflux, a reduction in levels of nuclear cadmium and a reduction in DNA cadmium content were observed in cells isolated from the testes of rats made resistant to cadmium carcinogenesis by zinc treatment. The DNA hypomethylating agent, deoxyazacytidine, caused both a marked increase in the synthesis of metallothionein, the protein most frequently associated with cadmium tolerance, and cellular tolerance to cadmium. Analysis of restriction enzyme digests of deoxyazacytidine-treated DNA indicated that this tolerance coincided with a hypomethylation of the MT gene, a condition clearly associated with enhanced expressibility. It was shown that, like the rat, mouse and monkey testes, the hamster ovaries are deficient in metallothionein. Hamster ovaries undergo an acute phase response to cadmium similar to that of the testes. An absence of metallothionein in the rat prostate was also established. Thus, a consistent absence of metallothionein in targets of cadmium toxicity and carcinogenesis is observed and the inability to express the metallothionein gene is probably a very important factor in susceptibility of a given tissue to cadmium carcinogenesis.